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| United States Patent |
5,541,305
|
|
Yokota
, et al.
|
July 30, 1996
|
Composition compatible with blood
Abstract
A material compatible with blood obtained by heparinizing a polymer having
quarternary ammonium groups with an alkali metal salt or an alkaline earth
metal salt of heparin or the analog by ion exchange is provided. The
equivalent ratio (M/S) of alkali metal atoms or alkaline earth metal atoms
(M) in the heparin or the analog bonded to the polymer to sulfur atoms (S)
in heparin or the analog bonded to the polymer is 0.4 or less.
| Inventors:
|
Yokota; Hideyuki (Ohtsu, JP);
Tanaka; Masakazu (Ohtsu, JP)
|
| Assignee:
|
Toyo Boseki Kabushiki Kaisha (JP)
|
| Appl. No.:
|
412513 |
| Filed:
|
March 29, 1995 |
Foreign Application Priority Data
| Jan 16, 1991[JP] | 3-017136 |
| May 20, 1991[JP] | 3-145528 |
| Current U.S. Class: |
536/21; 523/112; 536/112; 536/122 |
| Intern'l Class: |
A61K 031/725; C08B 037/10 |
| Field of Search: |
514/54,56
523/112
536/21,112,122
|
References Cited
U.S. Patent Documents
| 3755218 | Aug., 1973 | Yen et al. | 428/35.
|
| 4118485 | Oct., 1978 | Eriksson et al. | 514/56.
|
| 4613665 | Sep., 1986 | Larm | 536/20.
|
| 4654327 | Mar., 1987 | Teng | 514/56.
|
| 4720512 | Jan., 1988 | Hu et al. | 523/112.
|
| 4871357 | Oct., 1989 | Hsu et al. | 604/266.
|
| 5069899 | Dec., 1991 | Whitbourne et al. | 424/56.
|
| 5128408 | Jul., 1992 | Tanaka et al. | 525/54.
|
| 5159050 | Oct., 1992 | Onwumere | 528/67.
|
| 5159051 | Oct., 1992 | Onwumere et al. | 528/67.
|
| Foreign Patent Documents |
| 0338418 | Oct., 1989 | EP.
| |
| 2364939 | Sep., 1976 | FR.
| |
| 2610698 | Sep., 1976 | DE.
| |
| 49-38945 | Apr., 1974 | JP.
| |
| 52-36779 | Sep., 1977 | JP.
| |
| 52-36777 | Sep., 1977 | JP.
| |
| 58-92363 | Jun., 1983 | JP.
| |
| 1-131226 | May., 1989 | JP.
| |
Other References
Jpn. Kokai Tokkyo Koho Chem. Ab. 96(24): 205450a (1982).
Masuhara et al; Chem. Ab, 81:82408y (1974).
Toray; Chem. Ab. 94:77556n (1981).
Toray; Chem. Ab. 96:223331s (1982).
Langer et al (Eds); Med. Appl. Controlled Rel. vol. II pp. 77-106 (1984).
Imanishi et al; Chem. Ab. 104:155913q (1986).
Terumo; Chem. Ab. 97:11884v (1982).
Hu et al; Chem. Ab. 112:42675k (1990).
Cohn et al; Chem Ab. 115:78965f (1991).
|
Primary Examiner: Kunz; Gary L.
Assistant Examiner: Fonda; Kathleen Kahler
Attorney, Agent or Firm: Leydig, Voit & Mayer, Ltd.
Parent Case Text
This is a continuation of application Ser. No. 07/820,515 filed on Jan. 14,
1992, now abandoned.
Claims
What is claimed is:
1. A composition compatible with blood prepared by ion exchange
complexation of a polymer having quaternary ammonium groups with an alkali
metal salt of a polyanion selected from the group consisting of heparin,
chondroitin sulfate, dextran sulfate, and polyvinyl alcohol sulfate,
wherein said polymer having quaternary ammonium groups is prepared by
quaternizing a polymer containing tertiary amino groups with a
quaternizing agent, and
wherein the equivalent ratio, M/S, of alkali metal atoms (M) to sulfur
atoms (S) in the composition is 0.4 or less.
2. A composition compatible with blood according to claim 1, wherein the
polymer having quaternary ammonium groups is a polyurethane or
polyurethaneurea having quaternary ammonium groups obtained by
quaternizing the tertiary amino groups of a polyurethane or
polyurethaneurea,
wherein the polyurethane or the polyurethaneurea is obtained by reacting a
polyaminoetherpolyol that has at least two functional groups that react
with isocyanato groups with a polyisocyanate, and
wherein the polyaminoetherpolyol is obtained by condensation of diols
containing at least 30 mol % amino alcohol represented by a structure
selected from the group consisting of
##STR7##
wherein R.sub.2 is an alkyl group having 1 to 15 carbon atoms.
3. A composition compatible with blood according to claim 1, wherein the
polymer having quaternary ammonium groups is a polyurethane or
polyurethaneurea having quaternary ammonium groups obtained by
quaternizing at least a part of the tertiary amino groups in a
polyurethane or polyurethaneurea with an alkyl halide or an active ester,
wherein the polyurethane or the polyurethaneurea is prepared by reacting a
diisocyanate, a polysiloxane having a hydroxyl group or an amino group at
one or more of its molecular termini, and a polyaminoetherpolyol having
tertiary amino groups.
4. A composition compatible with blood according to claim 1, wherein the
polymer having quaternary ammonium groups contains either a polyurethane
or a polyurethaneurea having quaternary ammonium groups, and a
polytetramethylene glycol.
5. A composition compatible with blood according to claim 2, wherein the
total number of carbon atoms of two side chains bonded to a quaternary
nitrogen atom of a polymer having quaternary ammonium groups is 5 to 16,
in which one chain is bonded to a tertiary nitrogen atom of the polymer
having tertiary amino groups and the other side chain is derived from the
quaternizing agent.
6. A composition compatible with blood according to claim 1, wherein the
ion exchange complexation is carried out in a mixed solvent of a
water-soluble organic solvent and water.
7. A composition compatible with blood obtained by ion exchange
complexation of a polymer having quaternary ammonium groups with an alkali
metal salt of a polyanion selected from the group consisting of heparin,
chondroitin sulfate, dextran sulfate, and polyvinyl alcohol sulfate,
wherein the polymer is a polyurethane or a polyurethaneurea obtained by
quaternizing at least a part of the tertiary amino groups in the polymer
with an alkyl halide having 1 to 10 carbon atoms,
wherein the polyurethane or the polyurethaneurea is obtained by reacting a
polyaminoetherpolyol that has at least two functional groups that react
with isocyanato groups with a polyisocyanate, and
wherein the polyaminoetherpolyol contains, as a diol component, at least 30
mol % of an amino alcohol represented by the structure
##STR8##
wherein R.sub.1 and R.sub.3 are independently alkyl groups with 1 to 5
carbon atoms, and R.sub.2 is an alkyl groups with 1 to 15 carbon atoms, an
aralkyl group with 7 to 15 carbon atoms, or an aryl group with 6 to 15
carbon atoms,
wherein the total number of carbon atoms of two side chains bonded to a
quaternary nitrogen atom of a polymer having quaternary ammonium groups is
5 to 16, in which one chain is bonded to a tertiary nitrogen atom of the
polymer having tertiary amino groups and the other side chain is derived
from the quaternizing agent, and
wherein the equivalent ratio, M/S, of alkali metal atoms (H) to sulfur
atoms (S) in the composition is 0.4 or less.
8. A composition compatible with blood according to claim 7, wherein the
alkyl halide has 2 to 8 carbon atoms.
9. A composition compatible with blood according to claim 7, wherein the
total number of carbon atoms of said two side chains bonded to a
quaternary nitrogen atom of a polymer having quaternary ammonium groups is
6 to 14.
10. A composition compatible with blood according to claim 7, wherein the
polyaminoetherpolyol has a molecular weight of from 200 to 8,000.
11. A composition compatible with blood according to claim 7, wherein the
polyaminoetherpolyol has a molecular weight of from 500 to 4,000.
12. A composition compatible with blood according to claim 7, wherein the
tertiary amino groups of the polyaminoetherpolyol precursor of the
polyurethane or the polyurethaneurea are present in an amount of 0.05 to
5.00 mmol/g.
13. A composition compatible with blood according to claim 7, wherein the
tertiary amino groups of the polyaminoetherpolyol precursor of the
polyurethane or the polyurethaneurea are present in an amount of 0.1 to
3.0 mmol/g.
14. A composition compatible with blood according to claim 7, wherein 10%
or more of the tertiary amino groups are quaternized.
15. A composition compatible with blood according to claim 7, wherein 20%
or more of the tertiary amino groups are quaternized.
16. A composition compatible with blood according to claim 7, wherein the
alkali metal salt of heparin is selected from the group consisting of a
sodium salt of heparin and a potassium salt of heparin.
17. A composition compatible with blood according to claim 7, wherein the
ion exchange complexation is carried out in a mixed solvent of a
water-soluble organic solvent and water.
18. A composition compatible with blood according to claim 17, wherein the
water-soluble organic solvent is tetrahydrofuran, and the ratio of the
water to the tetrahydrofuran is from 20/1 to 3/7.
19. A composition compatible with blood according to claim 18, wherein the
ratio of the water to the tetrahydrofuran is from 10/1 to 3/5.
20. A composition compatible with blood according to claim 1, wherein the
polymer having quaternary ammonium groups is a film.
21. A composition compatible with blood according to claim 7, wherein the
polymer having quaternary ammonium groups is a film.
Description
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to a material compatible with blood for
medical use, which is brought into contact with an organism or a vital
component, and more particularly to a material compatible with blood which
has satisfactory anti-blood-clotting and mechanical properties.
2. Description of the Prior Art
In recent years, polymer materials excellent in moldability, elasticity,
flexibility, and the like have been widely used as materials for medical
use. Particularly, polymer materials of this type have been expected to be
used in greater amounts as disposable containers such as an injection
case, a blood bag, and a heart catheter, as well as artificial organs such
as an artificial kidney, an artificial lung, an auxiliary circulating
unit, and as artificial blood vessels. When the materials are used for
medical purposes, various kinds of reactions that may compromise the
vitality and/or viability of an organism may occur. In the case of blood,
for example, a compatibility with blood is required. Anti-coagulation
polymer materials provided hitherto can be obtained by the following three
methods: (1) bonding heparin or an analog thereof to the surface of the
polymer material; (2) applying a negative charge to the surface of the
polymer material; and (3) making the surface of the polymer material
inactive. The material of the present invention is obtained by (1). Method
(1) is divided into three categories: (A) blending the polymer material
with heparin or an analog thereof; (B) ion-bonding heparin or an analog
thereof to a cationic group in the polymer material; and (C) covalent
bonding heparin or an analog thereof to the polymer material. However, in
anti-blood-clotting polymer materials obtained in Methods (A) and (B),
heparin or the analog is detached from the surface of the polymer material
when used over a long period of time under physiological conditions, so
that these materials are inappropriate as medical materials which are used
by being fixed in vivo. In contrast, in materials compatible with blood
obtained in Method (C), heparin or the analog thereof is covalently bonded
to the polymer material, so that these materials have an advantage in that
heparin or the analog are not likely to be detached from the material.
However, according to the conventional covalent bond, conformational
changes are given to D-glucosamine and D-glucuronic acid which is heparin
components, so that the compatibility with blood are minimized.
SUMMARY OF THE INVENTION
The material compatible with blood of this invention, which overcomes the
above-discussed and numerous other disadvantages and deficiencies of the
prior art, is obtained by heparinizing a polymer having quaternary
ammonium groups with an alkali metal salt or an alkaline earth metal salt
of heparin or an analog thereof by ion exchange, the polymer being
obtained by quaternizing tertiary amino groups of a polymer with a
quaternizing agent, wherein the equivalent ratio of alkali metal atoms or
alkaline earth metal atoms (M) in heparin or the analog thereof bonded to
the polymer to sulfur atoms (S) in heparin or an analog thereof bonded to
the polymer (M/S) is 0.5 or less.
In a preferred embodiment, the polymer having quaternary ammonium groups is
a polyurethane or a polyurethaneurea having quaternary ammonium groups
obtained by quaternizing tertiary amino groups of a polyurethane or a
polyurethaneurea with a quaternizing agent; the polyurethane or the
polyurethaneurea contains as its main components a polyaminoetherpolyol, a
compound having at least two functional groups capable of reacting with
isocyanato groups, and a polyisocyanate; and the polyaminoetherpolyol is
obtained by condensation of diols and contains at least 30 mol% amino
alcohol represented by the general formula (I):
##STR1##
wherein R.sup.1 and R.sup.3 are independently alkyl groups with 1 to 5
carbon atoms, and R.sup.2 is an alkyl group, an aralkyl group, or an aryl
group with 1 to 15 carbon atoms.
In a preferred embodiment, the polymer having quaternary ammonium groups is
a polyurethane or a polyurethaneurea having quaternary ammonium groups
obtained by quaternizing at least a part of the tertiary amino groups in a
polyurethane or a polyurethaneurea with an alkyl halide or an active
ester, wherein the polyurethane or the polyurethaneurea contains as its
main components a diisocyanate, a polysiloxane having a hydroxyl group or
an amino group at, at least, one of its molecular termini, and a
polyaminoetherpolyol having tertiary amino groups.
In a preferred embodiment, the polymer having quaternary ammonium groups
contains as its component polytetramethylene glycol.
In a preferred embodiment, the total of the number of carbon atoms of the
two side chains bonded to quaternary nitrogen atoms of the polymer having
quaternary ammonium groups is 5 to 16, in which one side chain is bonded
to the tertiary nitrogen atom of the polymer having tertiary amino groups
and the other side chain is derived from the quaternizing agent.
In a preferred embodiment, the coefficient of water absorption of the
polymer having quaternary ammonium groups is 6% by weight or less.
In a preferred embodiment, the heparinization is carried out in a mixed
solvent of water-soluble organic solvent and water.
Thus, the invention described herein makes possible the objective of (1)
providing a material compatible with blood which can maintain excellent
compatibility with blood for a long period of time.
DESCRIPTION OF THE PREFERRED EMBODIMENTS
The present invention will be described in detail below.
The material compatible with blood of the present invention is a material
obtained by heparinizing a polymer having quaternary ammonium groups with
an alkali metal salt or an alkaline earth metal salt of heparin or an
analog thereof.
The polymer having quaternary ammonium groups is a polymer in which
tertiary amino groups of a polymer having tertiary amino groups are
quaternized. The polymer is preferably polyurethane or polyurethaneurea.
The polyurethane or polyurethaneurea contains as its main components a
polyaminoetherpolyol, a compound having at least two functional groups
capable of reacting with isocyanato groups, and a polyisocyanate.
The polyaminoetherpolyol is a polyetherpolyol having tertiary amino groups,
and preferably contains as its diol component an amino alcohol represented
by the following general formula (I).
##STR2##
In the general formula (I), examples of the alkyl groups with 1 to 5 carbon
atoms represented by R.sup.1 and R.sup.3 include saturated lower alkyl
groups such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertiary
butyl, pentyl, and isopentyl. Examples of alkyl groups with 1 to 15 carbon
atoms represented by R.sup.2 include the above saturated lower alkyl
groups; chain or branch alkyl groups such as hexyl, heptyl, octyl, nonyl,
decyl, undecyl, dodecyl, tridecyl, tetradecyl, and pentadecyl; and
saturated cycloalkyl groups such as cyclopentyl, cyclohexyl, and
cycloheptyl. Examples of the aralkyl group represented by R.sup.2 include
benzyl and phenetyl, and these groups can be substituted with alkyl groups
such as methyl, ethyl, and propyl. Examples of the aryl group represented
by R.sup.2 include phenyl and naphthyl, and these groups can be
substituted with alkyl groups such as methyl, ethyl, and propyl. Among
them, the alkyl groups with 1 to 15 carbon atoms are preferred.
Examples of the tertiary amino alcohol represented by the general formula
(I) include 3-methyl-3-aza-1,5-pentanediol, 3-ethyl-3-aza-1,5-pentanediol,
3-propyl-3-aza-1,5-pentanediol, 3-isobutyl-3-aza-1,5-pentanediol,
3-n-pentyl-3-aza-1,5-pentanediol, 3-n-hexyl-3-aza-1,5-pentanediol,
3-cyclohexyl-3-aza-1,5pentanediol, 3-phenyl-3-aza-1,5-pentanediol,
3-benzyl-3-aza-1,5-pentanediol, 4-methyl-4-aza-2,6-heptanediol,
4-ethyl-4-aza-2,6-heptanediol, 4-n-propyl-4-aza-2,6-heptanediol,
4-isopropyl-4-aza-2,6-heptanediol, 4-n-butyl-4-aza-2,6-heptanediol,
4-isobutyl-4-aza-2,6-heptanediol, 4-hexyl-4-aza-2,6-heptanediol,
4-cyclo-hexyl-4-aza-2,6-heptanediol, 4-benzyl-4-aza-2,6-heptanediol,
4-phenyl-4-aza-2,6-heptanediol, and 4-n-lauryl-4-aza-2,6-heptanediol
The polyaminoetherpolyol can contain as its diol component a compound
represented by the following general formula (II) or (III) in addition to
the amino alcohol represented by the general formula (I).
##STR3##
wherein R.sup.4 is an alkylene group with 2 to 20 carbon atoms, R.sup.5 is
an alkylene group with 2 to 5 carbon atoms, and m is an integer of 2 or
more.
Examples of the diol represented by the general formula (II) include
alkylene glycols such as ethylene glycol, propylene glycol, tetramethylene
glycol, 1,6-hexanediol, and neopentyl glycol. Examples of the diol
represented by the general formula (III) include diethylene glycol,
triethylene glycol, polyethylene glycol having a molecular weight of 200
to 2,000, dipropylene glycol, tripropylene glycol, polypropylene glycol
having a molecular weight of 200 to 1,000, polytetramethylene glycol
having a molecular weight of 200 to 1,000, and polyhexamethylene glycol
having a molecular weight of 200 to 1,000.
The polyaminoetherpolyo1 preferably contains at least 30 mol% amino alcohol
represented by the general formula (I). When the content of the amino
alcohol is less than 30 mol%, the content of the tertiary amino groups in
the polyurethane or polyurethaneurea is decreased, resulting in the
decrease in the amount of heparin or the analog which is bonded when the
polyurethane or polyurethaneurea is heparinized. Thus, a material having a
satisfactory blood compatibility cannot be obtained.
The polyaminoetherpolyol preferably has a molecular weight of 200 to 8,000,
and more preferably 500 to 4,000. The content of nitrogen atoms of
tertiary amino groups in the polyaminoetherpolyol is preferably 1.1 to
10.0 mmol/g, and more preferably 1.5 to 7.8 mmol/g.
Moreover, polyaminoetherpolyol is contained in the polyurethane or the
polyurethaneurea so that the tertiary amino groups present in the
molecules of the polyaminoetherpolyol are contained in the polyurethane
molecule or the polyurethaneurea molecule preferably in an amount of 0.05
to 5.00 mmol/g, and more preferably 0.1 to 3.0 mmol/g. Moreover, the
polyaminoetherpolyol is contained in polyurethane or polyurethaneurea
preferably in an amount of 1 to 90% by weight, and more preferably 5 to
70% by weight.
Examples of the compound having at least two functional groups capable of
reacting with isocyanato groups, which is a component of the polyurethane
or the polyurethaneurea, include a polysiloxane or a polyoxyalkylene
having a hydroxyl group or an amino group at, at least, one of its
molecular termini, a poly esterdiol, and a polylactonediol. Among them,
the polysiloxane or the polyoxyalkylene having a hydroxyl group or an
amino group at both termini is preferred. These compounds form a soft
segment in the polyurethane or the polyurethaneurea. The polysiloxane
having a hydroxyl group or an amino group at both termini is preferably
represented by the following general formula (IV):
##STR4##
wherein X and Y are independently --O, --NH.sub.2, or substituted amino
groups having 2 to 10 carbon atoms; R.sup.6 and R.sup.8 are independently
an alkylene group, an oxyalkylene group, an aralkylene group, or an
arylene group having 2 to 10 carbon atoms; R.sup.7 is an alkyl group, an
aryl group or an aralkyl group having 1 to 10 carbon atoms; and n is an
integer of 5 to 300.
The molecular weight of the polysiloxane represented by the general formula
(IV) is preferably 200 to 20,000, more preferably 500 to 8,000, and most
preferably 1,000 to 4,000. The content of the polysiloxane represented by
the general formula (IV) in the resulting polyurethane or the
polyurethaneurea is preferably 20 to 95% by weight, and more preferably 30
to 85% by weight.
Examples of the polyoxyalkylene having a hydroxyl group or an amino group
at both termini include polyethylene glycol, polypropylene glycol,
polytetramethylene glycol, or copolymers thereof. Among them,
polytetramethylene glycol is preferred. The molecular weight of the
polyoxyalkylene having a hydroxyl group or an amino group at both termini
is preferably 200 to 20,000, more preferably 500 to 8,000, and most
preferably 1,000 to 4,000. The content of the polyoxyalkylene in the
resulting polyurethane or the polyurethaneurea is preferably 20 to 95% by
weight, and more preferably 30 to 85% by weight.
The polyesterdiol can be obtained by the reaction between diols and
dicarboxylic acids or ester-forming derivatives. The diols preferably have
2 to 15 carbon atoms. Examples of the diols include ethylene glycol,
propylene glycol, tetramethylene glycol, pentamethylene glycol,
2,2-dimethyltrimethylene glycol, hexamethylene glycol, decamethylene
glycol, 1,4-dihydroxycyclohexane, and 1,4-dihydroxymethylcyclohexane.
Examples of the dicarboxylic acids or ester-forming derivatives include
aliphatic dicarboxylic acids such as cebacic acid, adipic acid,
dodecanedicarboxylic acid, glutaric acid, succinic acid malonic acid,
oxalic acid, and azeliac acid; aromatic dicarboxylic acids such as
terephthalic acid and isophthalic acid; or halides thereof, active esters
thereof, and amides thereof.
Examples of the polylactonediol include polylactonediol obtained by the
ring-opening polymerization of .epsilon.-caprolactone, etc.
As the polyisocyanate, all of the polyisocyanates used for producing
conventional polyurethane and polyisocyanates which will be developed in
the future can be used. Among them, diisocyanates are preferred. Examples
of diisocyanates include ethylene diisocyanates, trimethylene
diisocyanate, tetramethylene diisocyanate, pentamethylene diisocyanate,
octamethylene diisocyanate, undecamethylene diisocyanate, dodecamethylene
diisocyanate, 3,3'-diisocyanatopropylether, cyclopentane-1,3-diisocyanate,
cyclohexane-1,4-diisocyanate, 2,4-tolylene diisocyanate, 2,6-tolylene
diisocyanate, a mixture of 2,4-tolylene diisocyanate and 2,6-tolylene
diisocyanate, xylylene-1,4-diisocyanate, xylylene-1,3-diisocyanate,
4,4-diphenylmethane diisocyanate, 4,4-diphenylpropane diisocyanate,
4-isocyanatobenzyl isocyanate, m-phenylene diisocyanate, p-phenylene
diisocyanate, naphthalene-1,4-diisocyanate, and
naphthalene-1,5-diisocyanate.
The polyurethane or polyurethaneurea can contain, if necessary, other
components having functional groups capable of reacting with isocyanato
groups. Examples of these components include low molecular weight
polyamines, low molecular weight polyols, and low molecular weight amino
alcohols. These compounds extend a chain of the polyurethane or
polyurethaneurea. All of the known and novel compounds can be applicable.
Among polyols, diols are preferred. As for diols, examples include
ethylene glycol, propylene glycol, tetramethylene glycol, 1,5-heptanediol,
1,6-hexanediol, 1,10-decanediol, 1,4-dihydroxycyclohexane,
1,4-dihydroxymethylcyclohexane, diethylene glycol, and triethylene glycol.
Among polyamines, diamines are preferred. As for diamines, examples
include ethylene diamine, propylene diamine, butylene diamine,
hexamethylene diamine, xylylene diamine, phenylene diamine, and
4,4'-diaminodiphenylmethane. In addition to these, diamines in a broad
sense such as hydrazine and dihydrazine of dicarboxylic acid (such as
oxalic dihydrazide, succinic dihydrazide, adipic dihydrazide, cebacic
dihydrazide, and isophthalic di-hydrazide) can be used. Examples of the
amino alcohol include methanolamine, 2-aminoethanol, 3-aminopropanol, and
4-aminobutanol.
The polyaminoetherpolyol can be produced as follows. First, an amino acid
represented by the general formula (I) or a mixture including the amino
alcohol and a diol represented by the general formula (II) or (III) and
other diols is provided and then a catalyst such as phosphorous acid is
added. The resulting mixture of the amino alcohol or the amino alcohol and
diol, and the catalyst is heated to a temperature in the range of
150.degree. to 270.degree. C. under ordinary pressure, and preferably
200.degree. to 250.degree. C. The mixture is allowed to react for 1 to 30
hours and preferably for 3 to 20 hours while distilling off generated
water, and then evacuated to 10 mmHg or less, preferably 3 mmHg or less
over 0.5 to 6 hours, preferably 1 to 4 hours. The mixture is allowed to
react for 1 to 10 hours under the above-mentioned pressure and
temperature, preferably 2 to 7 hours, thereby obtaining the
polyaminoetherpolyol.
A production method of the polyurethane or polyurethaneurea is not
particularly limited. For example, it can be produced as follows. The
polyaminoetherpolyol, the compound having at least two functional groups
capable of reacting with isocyanato groups, and the polyisocyanate are
reacted to obtain a prepolymer having isocyanato groups at both terminals.
It is preferred that this prepolymer is obtained by reacting each of the
materials so that the molar ratio of isocyanato group to hydroxyl group is
1.1 to 5.0 (preferably 1.5 to 3.0). This prepolymer is reacted with a low
molecular weight compound having at least two functional groups capable of
reacting with the isocyanato groups such as the above-mentioned low
molecular weight diols, diamines, and amino alcohols to extend a molecular
chain of the prepolymer, thereby obtaining polyurethane or
polyurethaneurea. The content of tertiary amino groups contained in the
resulting polyurethane or polyurethaneurea is preferably 0.05 to 5.0
mmol/g, more preferably 0.1 to 3.0 mmol/g, and most preferably 0.2 to 2.0
mmol/g.
The polymer having quaternary ammonium groups used in the present invention
is a polymer obtained by quaternizing tertiary amino groups of a polymer
having tertiary amino groups with a quaternizing agent. Examples of the
quaternizing agent include alkyl halides, cycloalkyl halides, and active
esters. Among them, alkyl halides and active esters are preferred, more
preferably alkyl halides having 1 to 10 carbon atoms, and most preferably
alkyl halides having 2 to 8 carbon atoms. These quaternizing agents can be
used in combination of two or more kinds.
The total of the number of carbon atoms of the two side chains bonded to
the quaternary nitrogen atom of the polymer having quaternary ammonium
groups is preferably 5 to 16, and more preferably 6 to 14. One side chain
is bonded to the tertiary nitrogen atom of the polymer having tertiary
amino groups and the other side chain is derived from the quaternizing
agent. When the polymer having quaternary ammonium groups is polyurethane
or polyurethaneurea in which tertiary amino groups are quaternized, and
the quaternizing agent is an alkyl halide, the total of the number of
carbon atoms of R.sup.2 of the amino alcohol represented by the general
formula (I) and the number of carbon atoms of the alkyl group derived from
the quaternizing agent is preferably 5 to 16, and more preferably 6 to 14.
When the total number of the carbon atoms is 4 or less, the coefficient of
water absorption of the resulting polymer having quaternary ammonium
groups exceeds 10%, so that, in the resulting material compatible with
blood, heparin or an analog thereof tends to be rapidly detached from the
polymer having quaternary ammonium groups. Therefore, the compatibility
with blood cannot be maintained for a long period of time, and mechanical
strength of the material compatible with blood tends to be decreased,
causing problems for practical use. In contrast, when the total number of
the carbon atoms is 17 or more, because of increased steric hindrance
between the tertiary amino groups of the polymer and the quaternizing
agent, the degree of quaternization cannot be improved. Therefore, the
amount of heparin or an analog thereof bonded to the resulting polymer
having quaternary ammonium groups tends to be decreased, and compatibility
with blood tends to be difficult.
The degree of quaternization of the tertiary amino groups is preferably 10%
or more, more preferably 20% or more, and most preferably 30% or more.
It is preferred that the coefficient of water absorption of the polymer
having quaternary ammonium groups is 6% by weight or less. When the
coefficient of water absorption of the polymer exceeds 6% by weight, in
the resulting material compatible with blood, heparin or an analog thereof
is rapidly eluted from the polymer, so that the compatibility with blood
cannot be maintained for a long period of time.
The quaternization can be effected before or after the molding of
polyurethane or polyurethaneurea. If the tertiary amino groups is
quaternized before the molding of polyurethane or polyurethaneurea, it is
done in a solvent such as dimethylformamide, etc., and if quaternized
after the molding of polyurethane or polyurethaneurea, it can be done
without a solvent respectively from room temperature to its boiling point.
The quaternizing agent can be preferably used in the proportion of 0.1 to
10.0 moles, and more preferably 0.5 to 5.0 moles per mole of tertiary
amino groups in the polymer.
Finally, the material compatible with blood of the present invention is
obtained by heparinizing the polymer in which the tertiary amino groups
are quaternized with an alkali metal salt or an alkaline earth metal salt
of heparin or an analog thereof. The alkali metal salt of heparin or the
analog thereof is preferably sodium salt or potassium salt of heparin or
the analog thereof, and the alkaline earth metal salt of heparin or the
analog thereof is preferably magnesium salt or calcium salt of heparin or
the analog thereof.
The heparinization can be effected by the following reaction system:
##STR5##
In the above reaction system, Hep-SO.sub.3 M is heparin or the analog,
P.sub.1 and P.sub.2 are side chains bonded to the quaternary nitrogen atom
of the polymer having quaternary ammonium groups, in which P.sub.1 is the
side chain bonded to the tertiary nitrogen atom of the polymer having
tertiary amino groups, and P.sub.2 is a group derived from the
quaternizing agent, A.sup.- is a counterion derived from the quaternizing
agent, and M.sup.+ is an alkali metal ion or an alkaline earth metal ion.
Hep-SO.sub.3.sup.- is substituted for A.sup.-, an anion of the polymer
having quaternary ammonium groups, and is bonded to the polymer by the
ionic bond. At this time, M.sup.+, a cation of Hep-SO.sub.3.sup.-, are
bonded to A.sup.- and become free. Thus, as the number of bonding sites
between the heparin and the polymer becomes greater, an M/S equivalent
ratio becomes smaller and the bond between heparin or an analog thereof
and the polymer becomes stronger, wherein M/A is an equivalent ratio of an
alkali metal atoms or alkaline earth metal atoms (M) in heparin or the
analog thereof bonded to the polymer to sulfur atoms (S) in heparin or the
analog thereof bonded to the polymer. Sulfur atoms are present in sulfate
groups (--OSO.sub.3 M) or sulfamino groups (--NHSO.sub.3 M) in heparin or
the analog thereof. When M is an alkali metal atom, the M/S equivalent
ratio is the molar ratio of alkali metal atoms in heparin or the analog
thereof bonded to the polymer to sulfur atoms in heparin or the analog
thereof bonded to the polymer. When M is an alkaline earth metal atom, the
M/S equivalent ratio is two times the molar ratio of alkaline earth metal
atoms in heparin or the analog thereof bonded to the polymer to sulfur
atoms in heparin or the analog thereof bonded to the polymer. Therefore,
M/S is an equivalent ratio of the number of the sulfate groups and the
sulfamino groups in heparin or an analog thereof which are not ion-bonded
to the polymer having quaternary ammonium groups to the total number of
the sulfate groups and the sulfamino groups in heparin or the analog
thereof.
The material obtained in the present invention is characterized in that the
M/S equivalent ratio of the material obtained in the present invention is
0.5 or less, and preferably 0.4 or less. The bond between heparin or an
analog thereof and the polymer can become appropriately strong by limiting
the M/S equivalent ratio in this range, the detachment of heparin or the
analog thereof from the polymer in vivo can be controlled, and the
material can be used as a material compatible with blood for a long period
of time.
The heparinization can be effected before and after the molding of the
polymer having quaternary ammonium groups. It is preferred that the
heparinization is effected by immersing a mold of the polymer having
quaternary ammonium groups into a solution of heparin or an analog thereof
described below. This solution, usually having a concentration of 0.1 to
10%, and preferably 0.5 to 5%, can be used. Although the reaction can
proceed at room temperature, it is more preferable that the reaction is
effected by heating to a temperature in the range of about 40.degree. to
100.degree. C. Examples of heparin or an analog thereof used include
derivatives such as heparin, heparin metal salt, 4-heparin, and 4-heparin
metal salt; heparinoids such as chondroitin sulfate and dextran sulfate;
and heparin or the analogues such as PVA sulfate.
As the solvent used for the heparinization, a mixed solvent of water and
water-soluble organic solvents, such as acetone, ethanol, tetrahydrofuran,
dimethylformamide, or dimethylacetamide can be used.
Among them, a mixed solvent of water with tetrahydrofuran,
dimethylacetamide, or dimethylformamide is preferred. In order to realize
the M/S equivalent ratio of 0.5 or less, which is the characteristic of
the present invention, the mixed solvent of water with tetrahydrofuran is
most preferable.
A mixed ratio of water to the organic solvent is 20/1 to 3/7 in a volume
ratio, and preferably 10/1 to 3/5.
In the material compatible with blood of the present invention, the amount
of heparin bonded to the polymer having quaternary ammonium groups is
great, so that excellent compatibility with blood can be maintained for a
long period of time.
As general problems which arise when the polymer material is used being in
contact with blood, harmful effects caused by the elution of additives
(plasticizers, stabilizers, polymerization catalysts, etc.) and unreacted
substances (monomers, oligomers, etc.) of the material should be taken
into consideration in addition to the compatibility with blood. In the
material compatible with blood of the present invention, it is not
required that the plasticizers and the like are not added. Moreover, the
polymer material tends to be affected by complicated factors such as
decomposition by oxidation caused by radicals and oxygen and metabolism in
vivo. The material compatible with blood of the present invention contains
as its main components polyurethane or polyurethaneurea, so that chemical
stability is high. Thus, harmful eluted substances are hardly generated.
Furthermore, since the polyurethane or polyurethaneurea consists of a
polyaminoether segment with a high hydrophilicity, in which the tertiary
amino groups are quaternized, a polyether segment with a hydrophobicity,
and a urethane bond or a urea bond with a crystallinity, the phase
separation occurs in a solid phase and a microdomain structure is formed.
This structure is similar to that of vascular inner wall. Thus, the
anti-blood-clotting property can be expected from a structural point of
view.
EXAMPLES
Hereinafter, the present invention will be described by way of illustrating
examples. In the examples, unless specifically indicated, the term "parts"
refers to "parts by weight".
Example 1
First, 1,472 parts of 4-methyl-4-aza-2, 6-heptanediol, 591 parts of
1,6-hexanediol, and 12.3 parts of phosphorous acid were charged into an
autoclave. The mixture was heated and stirred at a temperature of
200.degree. to 220.degree. C. at atmospheric pressure under a stream of
nitrogen for 26 hours and allowed to react while distilling off generated
water. Then, the mixture was evacuated at 220.degree. C. from 760mmHg to
0.3 mmHg over 2 hours and was allowed to react at 220.degree. C. and 0.3
mmHg for another 3 hours. As described above, polyaminoetherdiol (a)
having an OH value of 57.3 and containing 6.11 mmol/g of nitrogen atoms of
the tertiary amino groups was obtained.
Next, 1,800 parts of polytetramethylene glycol with a number average
molecular weight of 1,500, 300 parts of the polyaminoetherdiol (a), 90.1
parts of 1,4-butanediol, 0.3 parts of dibutyltin dilaurate, and 554 parts
of 4,4'-diphenylmethane diisocyanate (hereinafter, referred to as MDI)
were dissolved in a mixed solvent of 1,994 parts of tetrahydrofuran
(hereinafter, referred to as THF) and 3,887 parts of dimethylformamide
(hereinafter, referred to as DMF). The mixture was allowed to react at
40.degree. C. under a stream of nitrogen for i hour and then at 60.degree.
C. for another 15 hours. As described above, a base polymer solution A
having a solid content of 32% and a viscosity of 3,200 poises (30.degree.
C.) was obtained. To this solution, DMF was added and stirred to obtain a
5% solution. Then, 10 g of 5% solution was uniformly applied onto the
surface area (100 cm.sup.2) of a glass plate held horizontal, after which
the resulting glass plate was dried under a stream of nitrogen at
40.degree. C. for 1 hour and at 60.degree. C. for 2 hours, followed by
drying under reduced pressure at 60.degree. C. for 15 hours to obtain a
base polymer film A.sub.1 with a thickness of 50 .mu.m. To 100 parts of
10% base polymer solution obtained by diluting the base polymer solution A
with DMF, 4.58 parts of hexyl iodide was added and allowed to react with
stirring at 70.degree. C., thereby quaternizing tertiary amino groups in
the base polymer. This solution was diluted with dioxane to obtain a 5%
solution. A polymer film A.sub.2 having quaternary ammonium groups with a
thickness of 50 .mu.m was obtained in the same way as in the base polymer
film A.sub.1.
About 0.2 g of the base polymer film A.sub.1, and 0.2 g of the polymer film
A.sub.2 having quaternary ammonium groups were carefully weighed
respectively, and each of the films was dissolved in 50 ml of a mixed
solvent of dioxane/ethanol (7:3 by volume), and measured for the content
of tertiary amino groups by means of a potentiometer (Hiranuma Seisakusho
Co.; Comtite-7). The solution of each polymer film was titrated with
N/10-HClO.sub.4 dioxane solution (commercially available 60% aqueous
HClO.sub.4 solution was diluted with dioxane so that the concentration was
0.1 normal) and the content of tertiary amino groups was calculated from
the point of inflection of the titration curve. The content of tertiary
amino groups of the base polymer film A.sub.1 was 0.67 mmol/g, and that of
the polymer film A.sub.2 having quaternary ammonium groups was 0.25
mmol/g. These results showed that the degree of quaternization was about
63%.
Next, the polymer film A.sub.2 having quaternary ammonium groups was
treated with heparin by being immersed in a 1% solution of heparin sodium
salt (THF/water=1/4 by weight was used as a solvent) at 60.degree. C. for
2 hours, thereby obtaining a heparinized polymer film A.sub.3 having
quaternary ammonium groups.
These resulting films were cut into circles with a diameter of 3 cm, and
these samples were thoroughly rinsed with distilled water and dried by
blotting up water on the film surfaces with filter paper. The film samples
were affixed to the center area of watch-glasses 10 cm in diameter. On the
surface of the film, 200 .mu.l of blood plasma of rabbit (Japanese white
species) to which citric acid had been added was placed, and to this, 200
.mu.l of an aqueous solution of calcium chloride at the concentration of
1/40 M was added. The watch glasses were floated on water in a water bath
at 37.degree. C. The water was gently stirred and the time needed for
coagulation of plasma to take place (i.e., until the plasma did not flow)
from the time of the addition of the aqueous solution of calcium chloride
was measured. The time that was needed for coagulation of plasma was
divided by the standard value. The standard value was obtained by
measuring the time needed for coagulation on the watch-glass without using
the film samples. The results are shown in Table 1 as the relative
coagulation time.
Next, the solution of the base polymer film A.sub.1, and the solution of
the polymer film A.sub.2 having quaternary ammonium groups were
respectively diluted with DMF to obtain 1% solutions. Then, glass beads of
40-60 mesh were immersed in 100 ml of the respective solutions for 30
minutes. The glass beads were filtered with a glass filter, dried at
40.degree. C. for 3 hours under a stream of nitrogen, and dried at
60.degree. C. for another 12 hours under reduced pressure, resulting in
polymer-coated glass beads. Half volume of glass beads coated with the
polymer having quaternary ammonium groups was treated by immersing in a 1%
solution of heparin sodium salt (THF/water=1/4 by weight was used as a
solvent) at 60.degree. C. for 2 hours, and then dried in the same way at
described above. To a test tube made of plastic, 200 mg of these coated
beads, 500 .mu.l of veronal buffer, and 500 .mu.l of serum (pooled serum
from healthy persons) were added, and the mixture was incubated at
37.degree. C. with gentle shaking for 30 minutes. Then, the amounts
produced of 50% Hemolytic unit of complement (abbreviated as CH.sub.50)
and of C3a and C5a (activated fragments of complement, of which production
means activation of complement) were measured. The results are shown in
Table 1. For the measurement of Ch.sub.50, the method of Meyer (M. M.
Meyer, "Complement and complement fixation", in Experimental Immune
Chemistry, 2nd Ed., p. 133, Charles C. Thomas Publisher, Stuttgart, 1964)
was used, and for the measurement of c3a and C5a, radioimmunoassay kits
available from the Upjohn Co. were used.
Moreover, the amounts of sulfur and sodium contained in the obtained
heparinized polymer film having quaternary ammonium groups were determined
by elemental analysis (ion chromatography) to obtain a content of S (% by
weight) and Na/S molar ratio. The results of the above are shown in Table
1.
TABLE 1
__________________________________________________________________________
Relative
coagulation
Activity of Content
time complement of S Na/S
(Glass =
CH.sub.50
C3a C5a (% by
Molar
1.00) (%)
(ng/ml)
(ng/ml)
weight)
ratio
__________________________________________________________________________
Example 1
Base polymer Film A.sub.1
2.90 94.0
350 200 -- --
Polymer film A.sub.2
3.40 100
200 120 -- --
having quaternary
ammonium groups
Heparinized polymer
>10 100
20 40 0.975
0.392
film A.sub.3 having
quaternary ammonium
groups
Example 2
Base polymer film B.sub.1
2.70 95.0
345 180 -- --
Polymer film B.sub.2
3.05 99.0
195 132 -- --
having quaternary
ammonium groups
Heparinized polymer
>10 99.0
25 38 1.03 0.379
film B.sub.3 having
quaternary ammonium
groups
Example 3
Base polymer film C.sub.1
2.70 95.0
345 180 -- --
Polymer film C.sub.2
3.20 100
190 130 -- --
having quaternary
ammonium groups
Heparanized polymer
>10 100
20 40 1.10 0.370
film C.sub.3 having
quaternary ammonium
groups
Comparative
Base polymer film D.sub.1
2.70 95.0
345 180 -- --
Example 1
Polymer film D.sub.2
3.05 99.0
195 132 -- --
having quaternary
ammonium groups
Heparinized polymer
>10 100
25 40 0.640
0.628
film D.sub.3 having
quaternary ammonium
groups
Comparative
Base polymer film E.sub.1
2.70 95.0
345 180 -- --
Example 2
Polymer film E.sub.2
3.05 99.0
195 132 -- --
having quaternary
ammonium groups
Heparinized polymer
>10 95.0
20 40 0.570
0.623
film E.sub.3 having
quaternary ammonium
groups
__________________________________________________________________________
Example 2
First, 8,040 parts of 3-n-butyl-3-aza-1,5-pentanediol and 10.3 parts of
phosphorous acid were charged into an autoclave. The mixture was heated
with stirring at a temperature of 200.degree. to 230.degree. C. at
atmospheric pressure under a stream of nitrogen for 26 hours and allowed
to react while distilling off generated water. Then, the mixture was
evacuated at 230.degree. C. from 760 mmHg to 0.3 mmHg over 2 hours and was
allowed to react at 230.degree. C. and 0.3 mmHg for another 3 hours. As
described above, polyaminoetherdiol (b) having an OH value of 64.7 and
containing 6.75mmol/g of nitrogen atoms of tertiary amino groups was
obtained.
Next, 3,240 parts of polytetramethylene glycol. with a number average
molecular weight of 1,800, 1,195 parts of MDI, 773.4 parts of the
polyaminoetherdiol (b), 0.3 parts of dibutyltin dilaurate, and 191.1 parts
of 1,4-butanediol were dissolved in a mixed solvent of 3,782 parts of THF
and 7,564 parts of DMF. The mixture was allowed to react under a stream of
nitrogen at 20.degree. C. for 1 hour, further at 40.degree. C. for 20
hours, thereby obtaining a base polymer solution B having a solid content
of 32% and a viscosity of 1,800 poises (30.degree. C.). This base polymer
solution B was treated with hexyl iodide in the same way as in Example 1
to be quaternized. Moreover, in the same way as in Example 1, a base
polymer film B.sub.1 and a polymer film B.sub.2 having quaternary ammonium
groups were obtained. The content of tertiary amino groups of the base
polymer film B.sub.1 was 1.08 mmol/g and that of the polymer film B.sub.2
having quaternary ammonium groups was 0.410 mmol/g, respectively. These
results showed that the degree of quaternization was about 62%. Then, a
heparinized polymer film B.sub.3 having quaternary ammonium groups was
obtained in the same way as in Example 1. Then, a relative coagulation
time, activity of complement, a content of S (% by weight), and Na/S molar
ratio were measured in the same way as in Example 1. The results are shown
in Table 1.
Example 3
In the same way as in Example 1, a base polymer film C.sub.1 was obtained
from the base polymer solution B obtained in Example 2, i.e., the base
polymer film C.sub.1 is just the same as the base polymer film B.sub.1.
The base polymer solution B was treated with ethyl iodide to be
quaternized in the same way as in Example 1, thereby obtaining a polymer
film C.sub.2 having quaternary ammonium groups. The content of tertiary
amino groups of the base polymer film C.sub.1 was 1.08 mmol/g and that of
the polymer film C.sub.2 having quaternary ammonium groups was 0.203
mmol/g. These results showed that the degree of quaternization was about
81%. This polymer film C.sub.2 having quaternary ammonium groups was
heparinized in the same way as in Example 1 to obtain a heparinized
polymer film C.sub.3 having quaternary ammonium groups. Then, a relative
coagulation time, activity of complement, and a content of S (% by
weight), and Na/S molar ratio were measured in the same as in Example 1.
The results are shown in Table 1.
Comparative Example 1
In the same way as in Example 1, a base polymer film D.sub.1 was obtained
from the base polymer solution B obtained in Example 2, i.e., the base
polymer film D.sub.1 is just the same as the base polymer film B.sub.1.
The base polymer solution B was treated with hexyl iodide to be
quaternized in the same way as in Example 1, thereby obtaining a polymer
film D.sub.2 having quaternary ammonium groups, i.e., the polymer film
D.sub.2 having quaternary ammonium groups is just the same as the polymer
film B.sub.2 having quaternary ammonium groups. The content of tertiary
amino groups of the base polymer film D.sub.1 was 1.08 mmol/g and that of
the polymer film D.sub.2 having quaternary ammonium groups was 0.410
mmol/g. These results showed that the degree of quaternization was about
62%. This polymer film D.sub.2 having quaternary ammonium groups was
heparinized with a 1% solution of heparin sodium salt
(dimethyl-acetamide/water=3/2 by weight was used as a solvent), thereby
obtaining a heparinized polymer film D.sub.3 having quaternary ammonium
groups. Then, a relative coagulation time, activity of complement, and a
content of S (% by weight), and Na/S molar ratio were measured in the same
as in Example 1. The results are shown in Table 1.
Comparative Example 2
In the same way as in Example 1, a base polymer film E.sub.1 was obtained
from the base polymer solution B obtained in Example 2, and a polymer film
E.sub.2 having quaternary ammonium groups were obtained in the same way as
in Example 1, i.e., the base polymer E.sub.1 and the polymer film E.sub.2
having quaternary ammonium groups are respectively the same as the base
polymer film B.sub.1 and the polymer film B.sub.2 having quaternary
ammonium groups. The content of tertiary amino groups of the base polymer
film E.sub.1 was 1.08 mmol/g, that of the polymer film E.sub.2 having
quaternary ammonium groups was 0.410 mmol/g, and the degree of
quaternization was 62%. In the same way as in Example 1, this polymer film
E.sub.2 having quaternary ammonium groups was heparinized with a 1%
solution of heparin sodium salt (water was used as a solvent) to obtain a
heparinized polymer film E.sub.3 having quaternary ammonium groups. Then a
relative coagulation time, activity of complement, a content of S (% by
weight), and Na/S molar ratio were measured in the same as in Example 1.
The results are shown in Table 1.
As is apparent from the results of Table 1, in this stage, both heparinized
polymer films having quaternary ammonium groups in Comparative Example 1
and Comparative Example 2 exhibited compatibility with blood comparable to
those of Examples 1, 2, and 3.
Each of the heparinized polymer films A.sub.3 to E.sub.3 having quaternary
ammonium groups was immersed in 200 ml of physiological saline and eluted
for 2 weeks while changing physiological saline every day. The results
obtained by measuring these eluted films for a relative coagulation time
and a content of S after being eluted for 2 weeks in the heparinized
polymer film having quaternary ammonium groups are shown in Table 2.
TABLE 2
__________________________________________________________________________
Comparative
Comparative
Example 1
Example 2
Example 3
Example 1
Example 2
Relative
Relative
Relative
Relative
Relative
coagulation
coagulation
coagulation
coagulation
coagulation
time of
time of
time of
time of
time of
Heparinized
Heparinized
Heparinized
Heparinized
Heparinized
polymer film
polymer film
polymer film
polymer film
polymer film
A.sub.3 having
B.sub.3 having
C.sub.3 having
D.sub.3 having
E.sub.3 having
quaternary
quaternary
quaternary
quaternary
quaternary
Immersion time
ammonium
ammonium
ammonium
ammonium
ammonium
(day) groups groups groups groups groups
__________________________________________________________________________
1 >10 >10 >10 >10 7.0
3 >10 >10 >10 >10 3.2
5 >10 >10 >10 7.0 2.8
7 >10 >10 >10 4.8 2.8
10 >10 >10 >10 4.8 2.8
14 >10 >10 >10 3.0 2.8
Content of S
0.970 1.01 1.02 0.251 0.104
after the
elution for 14
days (% by
weight)
__________________________________________________________________________
From the results of Tables 1 and 2, as the value of the Na/S molar ratio
became greater, the bond between the heparin and the polymer was weaker
and the heparin was likely to be released. Therefore, the effects of the
heparin were decreased as the immersion time became longer. After 2 hours,
the effects of the heparin had completely disappeared.
From the above, it is apparent that the heparinized polymer films having
quaternary ammonium groups of Examples 1, 2, and 3 possess satisfactory
compatibility with blood for a long period to time.
Example 4
First, 1,800 parts of polydimethylsiloxanediol with a number average
molecular weight of 1,800 represented by the following formula (V):
##STR6##
300 parts of the polyaminoetherdiol (a) of Example 1, 90.1 parts of
1,4-butanediol, 0.3 parts of dibutyltin dilaurate, and 554 parts of MDI
were dissolved in a mixed solvent of 1,994 parts of THF and 3887 parts of
DMF. The mixture was allowed to react under a stream of nitrogen at
40.degree. C. for 1 hour and at 60.degree. C. for another 15 hours,
thereby obtaining a base polymer solution F having a solid content of 32%
and a viscosity of 3,200 poises (30.degree. C). In the same way as in
Example 1, a base polymer film F.sub.1 and a polymer film F.sub.2 having
quaternary ammonium groups were obtained by using this base polymer
solution F. The content of tertiary amino groups of the base polymer film
F.sub.1 was 0.67 mmol/g and that of the polymer film F.sub.2 having
quaternary ammonium groups was 0.25 mmol/g. These results showed that the
degree of quaternization was about 63%.
Next, the oxygen permeation coefficients of these films were measured by
means of an apparatus for measuring gas permeation (Yanagimoto Co., Ltd.).
The oxygen permeation coefficient of the base polymer film F.sub.1 was
3.35.times.10.sup.-8 cm.sup.3 (STP) cm/cm.sup.2
.multidot.sec.multidot.cmHg, and that of the polymer film F.sub.2 having
quaternary ammonium groups was 3.78.times.10.sup.-8 (hereinafter, the
units "cm.sup.3 (STP).multidot./cm.sup.2 .multidot.sec.multidot.cmHg" will
be omitted).
Then, the polymer film F.sub.2 having quaternary ammonium groups was
treated with heparin by being immersed in a 1% solution of heparin sodium
salt (THF/water=1/10 by weight was used as a solvent) at 60.degree. C. for
2 hours, thereby obtaining heparinized polymer film F.sub.3 having
quaternary ammonium groups. The Na/S molar ratio of the heparinized
polymer film F.sub.3 -having quaternary ammonium groups was 0.382. These
resulting films were cut into circles with a diameter of 3 cm, and these
samples were thoroughly rinsed with distilled water and dried by blotting
up water on the film surfaces with filter paper. The film samples were
measured for a relative coagulation time in the same way as in Example 1.
The results are shown in Table 3.
Moreover, activity of the complement was measured in the same way as in
Example 1. The results are shown in Table 3.
Moreover, each of the resulting films was thoroughly dried and weighed,
then immersed in distilled water at 20.degree. C. for 24 hours. After that
the surface of each film was wiped and weighed. A coefficient of water
absorption was determined from the weight before and after being immersed.
The calculation of the coefficient of water absorption was conducted by
using following equation:
Coefficient of water absorption (%)={(W-D)/D}.times.100
In this equation, W is a film weight after being immersed, and D is a film
weight before being immersed. The results are shown in Table 3. The unit
of the oxygen permeation coefficients is cm.sup.3
(STP).multidot.cm/(cm.sup.2 .multidot.sec.multidot.cmHg).
TABLE 3
__________________________________________________________________________
Relative
Coefficient
coagulation
Activity of Coefficient
of Oxygen
time Complement of water
Na/S
permeability
(glass =
CH.sub.50
C3a C5a absorption
Molar
(.times. 10.sup.-8)
1.00) (%)
(ng/ml)
(ng/ml)
(%) ratio
__________________________________________________________________________
Example 4
Base polymer film F.sub.1
3.35 3.00 94.0
350 200 0.12 --
Polymer film F.sub.2
3.78 3.45 100
200 120 1.20 --
having quaternary
ammonium groups
Heparinized polymer
3.65 >10 100
20 40 1.33 0.382
film F.sub.3 having
quaternary ammonium
groups
Example 5
Base polymer film G.sub.1
3.07 2.78 95.0
345 180 0.15 --
Polymer film G.sub.2
3.12 3.11 99.0
195 132 0.76 --
having quaternary
ammonium groups
Heparinized polymer
3.00 >10 99.0
25 38 0.42 0.379
film G.sub.3 having
quaternary ammonium
groups
Example 6
Base polymer film H.sub.1
3.00 2.50 93.0
360 210 0.11 --
Polymer film H.sub.2
2.95 2.77 100
210 135 0.53 --
having quaternary
ammonium groups
Heparinized polymer
3.10 >10 100
23 43 0.56 0.369
film H.sub.3 having
quaternary ammonium
groups
Comparative
Base polymer film I.sub.1
3.07 2.78 95.0
345 180 0.15 --
Example 3
Polymer film I.sub.2
2.97 2.50 98.0
220 150 7.17 --
having quaternary
ammonium groups
Heparinized polymer
2.88 >10 100
35 60 14.31 0.624
film I.sub.3 having
quaternary ammonium
groups
Comparative
Base polymer film J.sub.1
<0.1 2.00 60.0
600 450 63.0 --
Example 4
Polymer film J.sub.2
<0.1 1.57 55.0
750 450 90.0 --
having quaternary
ammonium groups
Heparinized polymer
<0.1 >10 75.0
300 200 90.0 0.712
film J.sub.3 having
quaternary ammonium
groups
__________________________________________________________________________
Example 5
First, 3,240 parts of polydimethysiloxanediol represented by the formula
(V) with a number average molecular weight of 2,040, 1,195 parts of MDI,
773.4 parts of the polyaminoetherpolyol (b), 0.3 parts of dibutyltin
dilaurate, and 191.1 parts of 1,4-butanediol were dissolved in a mixed
solvent of 3,782 parts of THF and 7,564 parts of DMF. The mixture was
allowed to react at 20.degree. C. under a stream of nitrogen for 1 hour
and at 40.degree. C. for 20 hours, thereby obtaining a base polymer
solution G having a solid content of 32% and a viscosity of 1800 poises
(30.degree. C.). This base polymer solution G was treated in the same way
as in Example 1 to obtain a base polymer film G.sub.1 and a polymer film
G.sub.2 having quaternary ammonium groups. The content of tertiary amino
groups of the base polymer film G.sub.1 was 1.08 mmol/g and that of the
base polymer film G.sub.2 having quaternary ammonium groups was 0.410
mmol/g. These results showed that the degree of quaternization was about
62%. Then, a heparinized polymer film G.sub.3 having quaternary ammonium
groups was obtained by heparinizing the polymer film G.sub.2 having
quaternary ammonium groups (the Na/S molar ratio was 0.379) in the same
way as in Example 4. Then, a coefficient of oxygen permeability, a
relative coagulation time, activity of complement, and a coefficient of
water absorption were measured in the same way as in Example 4. The
results are shown in Table 3.
Example 6
First, 8,738 parts of 3-n-butyl-3-aza-1,5-pentanediol and 10.3 parts of
phosphorous acid were charged into an autoclave. The mixture was heated
and stirred at a temperature of 200.degree. to 230.degree. C. at a
constant. pressure under a stream of nitrogen for 26 hours and allowed to
react while distilling off generated water. Then, the mixture was
depressurized at 230.degree. C. from 760 mmHg to 0.3 mmHg over 2 hours and
was allowed to react at 230.degree. C. and 0.3 mmHg for another 3 hours.
As described above, polyaminoetherdiol (c) having an OH valence of 58.7
and containing 6.30mmol/g of nitrogen atoms of the tertiary amino groups
was obtained.
Next, 3,240 parts of polydimethylsiloxanediol with a number average
molecular weight of 2,040 represented by the formula (V), 1,195 parts of
MDI, 827.3 parts of the polyaminoetherdiol (c), 0.3 parts of dibutyltin
dilaurate, and 191.1 parts of 1,4-butanediol were dissolved in a mixed
solvent of 3,802 parts of THF and 7,604 parts of DMF. The mixture was
allowed to react at 20.degree. C. under a stream of nitrogen for 1 hour
and then at 40.degree. C. for another 20 hours. As described above, a base
polymer solution H having a solid content of 32% and a viscosity of 1,830
poises (30.degree. C.) was obtained. This base polymer solution H was
treated in the same way as in Example 1, thereby obtaining a base polymer
film H.sub.1 and a polymer film H.sub.2 having quaternary ammonium groups.
The content of tertiary amino groups of the base polymer film H.sub.1 was
1.08 mmol/g and that of the polymer film H.sub.2 having quaternary
ammonium groups was 0.410 mmol/g. These results showed that the degree of
quaternization was about 62%. Then, in the same way as in Example 4, a
heparinized polymer film H.sub.3 having quaternary ammonium groups was
obtained by heparinizing the polymer film H.sub.2 having quaternary
ammonium groups (the Na/S molar ratio was 0.369). Then, a coefficient of
oxygen permeability, a relative coagulation time, activity of complement,
and a coefficient of water absorption were measured in the same way as in
Example 4. The results are shown in Table 3.
Comparative Example 3
A base polymer film 11 was obtained in the same way was in Example 1 from
the base polymer solution G obtained in Example 5, i.e., the base polymer
film I.sub.1 is just the same as the base polymer film G.sub.1. The base
polymer solution G was treated with ethyl iodide to be quaternized in the
same way as in Example 1, thereby obtaining a polymer film I.sub.2 having
quaternary ammonium groups. The content of tertiary amino groups of the
base polymer film I.sub.1 was 1.08 mmol/g and that of the polymer film
I.sub.2 having quaternary ammonium groups was 0.210 mmol/g. These results
showed that the degree of quaternization was about 82%. Then, in the same
way as in Example 4, a heparinized polymer film I.sub.3 was obtained by
heparinizing the polymer film I.sub.2 having quaternary ammonium groups
(the Na/S molar ratio was 0.624). Then, a coefficient of oxygen
permeability, a relative coagulation time, activity of complement, and a
coefficient of water absorption were measured in the same way as in
Example 4. The results are shown in Table 3.
Comparative Example 4
First, 24 parts of acrylonitrile, 89 parts of acrylamide, and 126 parts of
dimethylsulfoxide were thoroughly mixed. To this mixture, 0.2 parts of
dodecylmercaptan as a chain transfer agent and 0.3 parts of bromoform as a
polymerization initiator were added. The mixture was photo-polymerized by
irradiating light with a high-voltage mercury lamp of 100 W at a distance
of 10 cm for 7 hours. The resulting photo-polymerized solution was poured
into a great amount of methanol, and precipitated and coagulated, thereby
obtaining 24.4 parts of a polymer. Ten g of this polymer was dissolved in
120 parts of dimethylsulfoxide, to which 5.0 parts of
dimethylaminoethylmethacrylate was added. This mixture was photo-grafted
by irradiating light with a high-voltage mercury lamp of 100 W at a
distance of 10 cm for 19 hours. The resulting photo-grafted solution was
poured into methanol, and precipitated and coagulated, thereby obtaining
12.8 parts of graft polymer. Then, the graft polymer was molded in the
same way as in Example 4 to obtain a base polymer film J.sub.1. The
resulting graft polymer was dissolved in dimethylformamide, to which ethyl
bromide was added to be quaternized. Then, the mixture was molded into a
polymer film J.sub.2 having quaternary ammonium groups. In the same way as
in Example 4, this polymer film J.sub.2 having quaternary ammonium groups
was heparinized to obtain a heparinized polymer film J.sub.3 having
quaternary ammonium groups (the Na/S molar ratio was 0.712).
Next, a coefficient of oxygen permeability, a relative coagulation time,
activity of complement, and a coefficient of water absorption were
measured in the same was as in Example 4. The results are shown in Table
3.
As is apparent from Table 3, the heparinized polymer film J.sub.3 having
quaternary ammonium groups of Comparative Example 4, which does not
contain polydimethylsiloxane units is poor in gas-permeability and
activates the complement. In contrast, the heparinized polymer films
having quaternary ammonium groups of Examples 4 to 6 possessed
satisfactory gas-permeability, the activity of complement being
suppressed. In this stage, the heparinized polymer films 13 having
quaternary ammonium groups of Comparative Example 3 possessed properties
comparable to those of Examples 4 to 6.
The heparinized polymer films F.sub.3 to J.sub.3 having quaternary ammonium
groups obtained in Examples 4 to 6 and Comparative Examples 3 and 4 were
immersed in 200 ml of physiological saline and eluted for 2 weeks while
changing physiological saline every day. The results obtained by measuring
a relative coagulation time of these eluted film are shown in Table 4.
TABLE 4
__________________________________________________________________________
Comparative
Comparative
Example 4
Example 5
Example 6
Example 3
Example 4
Relative
Relative
Relative
Relative
Relative
coagulation
coagulation
coagulation
coagulation
coagulation
time of
time of
time of
time of
time of
Heparinized
Heparinized
Heparinized
Heparinized
Heparinized
polymer film
polymer film
polymer film
polymer film
polymer film
F.sub.3 having
G.sub.3 having
H.sub.3 having
I.sub.3 having
J.sub.3 having
quaternary
quaternary
quaternary
quaternary
quaternary
Immersion time
ammonium
ammonium
ammonium
ammonium
ammonium
(day) groups groups groups groups groups
__________________________________________________________________________
1 >10 >10 >10 7.0 3.5
3 >10 >10 >10 2.8 2.0
5 >10 >10 >10 2.8 2.0
7 >10 >10 >10 2.8 2.0
10 >10 >10 >10 2.8 2.0
14 >10 >10 >10 2.8 2.0
__________________________________________________________________________
Table 4 presents data regarding the heparinized polymer films having
quaternary ammonium groups of Examples 4 to 6, which have a coefficient of
water absorption of 6% or less, as indicated therein; these films
possessed satisfactory compatibility with blood even after the elution in
the physiological saline for 2 weeks. In contrast, in the heparinized
polymer films having quaternary ammonium groups of Comparative Examples 3
and 4, which have a great coefficient of water absorption, the heparin was
rapidly eluted, so that the effects of the heparin disappeared.
As described above, it is apparent that the heparinized polymer films
having quaternary ammonium groups of Examples 4, 5, and 6 have
satisfactory gas-permeability and are compatible with blood for a long
period of time.
As is apparent from the above description, according to the present
invention, the material compatible with blood having a great amount of
bonded heparins can be provided. Thus, a high compatibility with blood can
be obtained without using the heparin together while the blood is
circulating in vivo, and moreover, the compatibility with blood can be
maintained for a long period of time. Furthermore, the: material has a
satisfactory mechanical property such as elasticity, and even when it is
brought into contact with body fluid such as blood, harmful eluted
substances are hardly generated.
Because of the above-mentioned advantages, the material compatible with
blood of the present invention can be widely applicable to various kinds
of apparatuses or equipment for medical use. More specifically, the
material can be used as sheets, tubes, or hollow fibers for blood dialysis
of renal failure patients; and as coating materials for adsorbing egesta
in the blood. In addition to such an artificial kidney, the material can
be used as film materials for an artificial lung (partition wall between
the blood and the oxygen) and sheet materials of a sheet lung for an
artificial heart-lung machine. Moreover, the material can be widely used
as aortic balloons, artificial blood vessels, blood bags, catheters,
cannulas, shunts, blood circuits, and coating materials used for these.
It is understood that various other modifications will be apparent to and
can be readily made by those skilled in the art without departing from the
scope and spirit of this invention. Accordingly, it is not intended that
the scope of the claims appended hereto be limited to description as set
forth herein, but rather that the claims be construed as encompassing all
the features of patentable novelty that reside in the present invention,
including all features that would be treated as equivalents thereof by
those skilled in the art to which this invention pertains.
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